Project Summary: Heart failure due to left ventricular systolic dysfunction (LVSD) is commonly associated with the development of pulmonary hypertension (LVSD-PH). However, the response of the right ventricle (RV) to increased pulmonary arterial pressure (PAP) at rest and during exercise is highly variable in LVSD-PH and remains poorly understood. When overt RV dysfunction at rest occurs it is associated with reduced exercise capacity, renal and hepatic dysfunction, and increased mortality. Patients with LVSD-PH will be studied in PITCH, the parent trial for this ancillary study. PITCH will test the hypothesis that compared to placebo, the pulmonary vasodilator tadalafil will improve outcomes in patients with LVSD-PH. This trial represents an ideal setting in which to determine how the RV responds to elevated PAP in LVSD-PH. We will employ a longitudinal, serial measurement study (at baseline and 3 months) using a multi-modality physiologic testing protocol consisting of cardiopulmonary exercise testing (CPET) and simultaneous echocardiography and blood draws at rest and during exercise. The underlying premise of this ancillary study is that abnormal pulmonary vasodilatory capacity, as reflected by steep PAP increment relative to cardiac output (i.e. PAP/CO or RV-PV reserve) with exercise, is a major determinant of RV dysfunction and adverse outcomes in HF, and therefore should be a therapeutic target. The goal of this research is to identify easily measured cardiopulmonary exercise testing (CPET) indices that reflect abnormal PAP/CO as well as vasoactive metabolites that mark abnormal PAP/CO. This proposal addresses an unmet clinical need for improved physiologic and circulating biomarkers to characterize RV-PV reserve in HF. Markers of RV- PV reserve may aid in earlier detection of RV dysfunction in HF and identify patients most likely to benefit from RV-afterload reducing therapies that have recently shown promise. Our experience in leading CPET and Echo core laboratories for multicenter trials will greatly facilitate completion of this multi-center ancillary study in 154 subjects at 15 sites. Our preliminary data demonstrate that CPET measurements during submaximal exercise closely reflect PAP/CO and may provide additive functional and prognostic significance to resting measurements. We have also identified candidate metabolic signatures of RV-PV reserve with a focus on metabolites from pathways involved in vasodilation. In Aim 1 we will define CPET parameters that reflect abnormal PAP/CO and assess their ability to predict 6 and 18 month AHEFT Clinical Composite Scores (HFCC score). Based on novel preliminary findings, in Aim 2 we will investigate the utility of vasoactive small molecules, including arginine metabolites and indoleamine 2,3- dioxygenase-dependent tryptophan metabolites, as biomarkers of RV-PV reserve and assess their prognostic significance in predicting long term HFCC scores. In Aim 3 we will determine whether 0-3 mo changes in echo, CPET, and metabolite markers of RV-PV reserve in the two treatment groups predict long term HFCC scores.